CD34⁺/CD38⁻ Acute Myelogenous Leukemia Cells Aberrantly Express Aurora Kinase A

Abstract 1886

Aurora kinase A (AURKA) plays a pivotal role in the mitotic processes during cell division. We previously showed that AURKA was aberrantly expressed in hematological malignant cells including those from acute myelogenous leukemia (AML) and acute lymphoblastic leukemia, compared with CD34⁺ hematopoietic stem/progenitor cells isolated from healthy volunteers. This study found that freshly isolated CD34⁺/CD38⁻ cells from individuals with AML (n=12) in which leukemia stem cells were supposed to be enriched expressed a greater amount of AURKA than their CD34⁺/CD38⁺ counterparts, as measured by real time RT-PCR. Blockade of AURKA by the specific inhibitor MLN8237 significantly inhibited proliferation and induced apoptosis of CD34⁺/CD38⁻ AML cells, as assessed by the clonogenic assay and detection of the cleaved form of poly (ADP-ribose) polymerase by Western blot analysis, respectively. In addition, exposure of CD34⁺/CD38⁻ AML cells to MLN8237 down-regulated levels of Bcl-2 family proteins and increased Bax/Bcl-2 expression ratio. Moreover, inhibition of AURKA by MLN8237 (30mg/kg for 14 consecutive days) impaired engraftment of CD34⁺/CD38⁻ AML cells in severely immunocompromised mice (n=5, 49±32% in control vs 18±16% in MLN8237 treated mice, P<0.05), and prolonged their overall survival (P<0.05), compared with vehicle treated mice. Taken together, AURKA may be a promising molecular target to eliminate chemotherapy-resistant CD34⁺/CD38⁻ AML cells.